Icotrokinra induces early and sustained pharmacodynamic responses in phase IIb study of patients with moderate-to-severe psoriasis

Abstract

BACKGROUNDIcotrokinra is the first and only targeted oral peptide that selectively binds the IL-23 receptor with high affinity to precisely inhibit IL-23 signaling. Icotrokinra demonstrated high rates of complete skin clearance and durable disease control in the phase IIb trial, FRONTIER-1, and its long-term extension, FRONTIER-2, in participants with moderate-to-severe plaque psoriasis. This study evaluated systemic and skin pharmacodynamic response of icotrokinra and its relationship to clinical response in FRONTIER participants.METHODSFRONTIER-1 participants received icotrokinra or placebo for 16 weeks. FRONTIER-2 followed participants for up to 1 year of treatment; placebo participants transitioned to icotrokinra after week 16. Systemic pharmacodynamic changes were assessed in serum through week 52. Skin pharmacodynamic changes were assessed using transcriptomic analysis of skin biopsies and protein quantification in tape-strip samples through week 16.RESULTSIcotrokinra dose-dependently reduced serum levels of the IL-23/IL-17 axis and psoriasis disease biomarkers through week 52, with maximal reductions observed with the highest 100 mg twice-daily dose. Proteomic analyses showed icotrokinra selectively blocked IL-23-driven inflammation without broader impacts on circulating proteins, including serum IL-23 levels. Sixteen weeks of icotrokinra, but not placebo, reduced expression of psoriasis-associated genes in lesional skin. Icotrokinra treatment also reduced psoriasis-relevant proteins in week 16 lesional skin tape-strips to levels comparable to nonlesional samples.CONCLUSIONIcotrokinra induced a dose-dependent pharmacodynamic response, with early (week 4) and sustained (week 52) reductions in biomarkers of IL-23 pathway activation and psoriasis disease severity, which correlated with clinical response.TRIAL REGISTRATIONClinicalTrials.gov: NCT05223868, NCT05364554.FUNDINGJohnson & Johnson.

Keywords: Biomarkers; Clinical Research; Clinical trials; Dermatology; Inflammation; Transcriptomics.

Figure 1. CONSORT diagram of FRONTIER-1 and FRONTIER-2 clinical trials.

Flowchart illustrates the number of participants randomized to each treatment group who were included in the analyses. BID, twice daily; Pt, patient; QD, once daily.

Figure 2. Serum levels of biomarkers relevant to psoriasis disease over time among participants receiving icotrokinra and placebo and broad protein quantification of icotrokinra-treated participant serum.

Serum levels of (A) IL-17A, (B) IL-17F, (C) IL-22, (D) BD-2, and (E) IL-23 among participants receiving icotrokinra and placebo were compared with baseline over time. (F) Olink Explore HT protein quantification in serum of icotrokinra-treated participants at week 52 versus week 0. Of the 5,420 proteins that were quantified, 11 proteins were significantly downregulated (adjusted P < 0.05; log₂ FC < –1) with icotrokinra after 52 weeks of treatment. (A–E) Estimated marginal means displayed. Error bars are model-based 95% confidence intervals. *Nominal P < 0.05 for all treatments versus baseline. ^†Nominal P < 0.01 for all treatments versus baseline. ^‡Nominal P < 0.001 for all treatments versus baseline. ^§Nominal P < 0.0001 for all treatments versus baseline. (F) Log₂ FC = 1 or –1 and adjusted P value = 0.05 thresholds are depicted with dotted lines. Enrichment statistics were based on Benjamini-Hochberg procedure. BD, beta-defensin; BID, twice daily; FC, fold change; PBO, placebo; PI, peptidase inhibitor; QD, once daily; CAMK1G, calcium/calmodulin dependent protein kinase IG; ENTHD1, ENTH domain-containing protein 1; FKBP1B, FKBP prolyl isomerase 1B; GPR15LG, G protein–coupled receptor 15 ligand.

Figure 3. GSVA scores of skin biopsies in lesional and nonlesional skin among participants receiving icotrokinra compared with placebo.

Gene set expression in lesional skin from icotrokinra-treated participants is more similar to nonlesional skin than lesional skin. GSVA, gene set variation analysis; BID, twice daily; NFKB, nuclear factor κB; PID, Pathway Interaction Database; QD, once daily; Th, T helper cells; TNF, tumor necrosis factor.

Figure 4. Protein changes in skin among participants receiving icotrokinra and placebo.

(A) BD-2 protein levels in skin of participants receiving icotrokinra compared with placebo at weeks 0 and 16. Comparisons of BD-2 protein levels (pg of BD-2/μg of total protein) between lesional and nonlesional skin and between week 0 and week 16 were performed using an unpaired t test. BD-2 protein levels were significantly reduced after 16 weeks of icotrokinra but not with placebo. (B–E) Protein expression measured by Olink Explore HT comparing (B) lesional versus nonlesional skin at week 0, (C) lesional skin from icotrokinra-treated participants at week 16 versus week 0, and (D) lesional skin from icotrokinra-treated participants at week 16 versus nonlesional skin at week 0. Psoriasis-relevant proteins were upregulated at week 0 in lesional skin compared with nonlesional, and they were downregulated after 16 weeks of icotrokinra, bringing protein expression to levels comparable to nonlesional skin. (E) GSVA scores of protein sets in skin of placebo- and icotrokinra-treated FRONTIER-1 participants and healthy volunteers. Skin from icotrokinra-treated participants was more similar to nonlesional than lesional skin. *Nominal P < 0.05 based on unpaired t test. (B–D) Log₂ FC = 1 or –1 and adjusted P value = 0.05 thresholds are depicted with dotted lines. Enrichment statistics were based on Benjamini-Hochberg procedure. ^aBD-2 pg/mL: total μg/mL. ^bAverage of 100 mg BID and placebo (PBO) nonlesional skin at week 0. ^cHealthy control (HC) skin tape-strip samples were obtained from sponsor healthy donor program at Johnson & Johnson (Protocol NOCOMPOUNDNAP1001). DEFB4, defensin beta 4; BID, twice daily; NFKB, nuclear factor κB; NL, nonlesional; PI, peptidase inhibitor; RQ, relative quantification; Th, T helper cells; TNF, tumor necrosis factor; W, week.

Figure 5. Levels of BD-2 and IL-22 in serum are correlated with PASI response among participants receiving icotrokinra.

(A and B) BD-2. (C and D) IL-22.Correlation between PASI change from baseline and biomarker change from baseline was performed using Pearson’s correlation. BD-2 and IL-22 log₂ FC from baseline were compared across all PASI percentage improvement categories, and adjusted P values were generated using Tukey’s multiple comparisons of means. Reductions in BD-2 and IL-22 were correlated with PASI improvement. **P < 0.01. ***P < 0.001. Correlation performed using Pearson’s correlation. Adjusted P values calculated using Tukey’s test for multiple comparisons of means. BD, beta-defensin; BID, twice daily; PASI, Psoriasis Area and Severity Index; QD, once daily.

Figure 6. Visual predictive check for longitudinal population PK/PD model describing the effect of icotrokinra on PASI and log₂ BD-2.

(A) PASI. (B) log₂ BD-2. BD, beta-defensin; BID, twice daily; CI, confidence interval; PASI, Psoriasis Area and Severity Index; PD, pharmacodynamics; PK, pharmacokinetics; QD, once daily.